Immunohistochemical staining for cytokeratin (CK) 34ssE12 has been routinely used to elucidate prostate basal cells for differentiation between non-invasive and invasive lesions. Our previous studies, however, revealed that some morphologically distinct basal cells observed on H&E-stained sections completely lacked CK34ssE12 expression. Our current study attempted to assess whether these basal cells would also lack the expression of other phenotypic markers, and whether basal cell alterations would affect the proliferation status of the associated tumor cells. Consecutive sections from prostate tumors with large basal cell clusters that were morphologically distinct in H&E sections but were completely negative for CK 34ssE12 were morphologically and immunohistochemically assessed with a panel of basal cell phenotypic and other markers. In addition to CK 34ssE12, these basal cells also completely lacked the expression of other phenotypic markers, including CK5, CK14, p63, and maspin, in contrast to adjacent basal cells, which were strongly positive for these markers. Tumors surrounded by basal cell layers that lack the expression of basal cell phenotypic markers showed a significantly higher rate of cell proliferation and mast cell infiltration than their counterparts. These findings suggest that basal cells might be targets of a variety of pathological alterations, which could significantly impact biological presentations of associated tumor cells.
"Compared to their non-disrupted counterparts, focally disrupted basal cell layers
showed a significantly lower frequency of tumor suppressor expression and
proliferation, but a significantly higher rate of degeneration and leukocyte
infiltration 33. In contrast, epithelial
cells overlying focally disrupted basal cell layers had a significantly higher rate
of proliferation and expression of tumor invasion related genes 33-34. Based on these and other findings, we have proposed that prostate tumor invasion or
progression is triggered by FBCLD induced auto-immunoreactions, which facilitate
formation of more aggressive cell clones or monoclonal proliferation of tumor stem
cells overlying focally disrupted basal cell layers. "
[Show abstract][Hide abstract] ABSTRACT: Our recent studies revealed that focal basal cell layer disruption (FBCLD) induced auto-immunoreactions represented a contributing factor for human prostate tumor progression and invasion. As the basement membrane surrounds and attaches to the basal cell layer, our current study assessed whether FBCLD would impact the physical integrity of the associated basement membrane. Paraffin sections from 25-human prostate tumors were subjected to double immunohistochemistry to simultaneously elucidate the basal cell layer and the basement membrane with corresponding biomarkers. The physical integrity of the basement membrane overlying FBCLD was examined to determine the extent of correlated alterations. Of a total of 89 FBCLD encountered, 76 (85 %) showed correlated alterations in the overlying basement membrane, which included distinct focal disruptions or fragmentations. In the remaining 13 (15%) FBCLD, the overlying basement membrane showed significant attenuation or reduction of the immunostaining intensity. The basement membrane in all or nearly all ducts or acini with p63 positive basal cells was substantially thicker and more uniform than that in ducts or acini without p63 positive basal cells, and also, a vast majority of the focal disruptions occurred near basal cells that lack p63 expression. These findings suggest that focal disruptions in the basal cell layer and alterations in the basement membrane are correlated events and that the physical and functional status of the basal cells could significantly impact the physical integrity of the overlying basement membrane. As the degradation of both the basal cell layer and the basement membrane is a pre-requisite for prostate tumor invasion or progression, ducts or acini with focally disrupted basal cell layer and basement membrane are likely at greater risk to develop invasive lesions. Thus, further elucidation of the specific molecules and mechanism associated with these events may lead to the development of a more effective alternative for repeat biopsy to monitor tumor progression and invasion.
International journal of biological sciences 02/2009; 5(3):276-85. · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The development of breast cancer is believed to be a multi-step process, sequentially progressing from normal to hyperplastic, to in situ, and to invasive stages. The progression from the in situ to invasive stage is believed to be triggered primarily, if not solely, by the overproduction of proteolytic enzymes by cancer cells, which cause degradation of the basement membrane. This theory is consistent with data derived from studies with cell cultures or animal models, while results from recent worldwide clinical trials with a variety of proteolytic enzyme inhibitors have been very disappointing, casting doubt on the validity of the enzyme theory. Based on our recent studies, we propose that breast tumor invasion is triggered by the following mechanisms and events: (1) the predisposition of genetic abnormalities in ME cell replenishment-related genes or other insults results in elevated focal degeneration of ME cells in some individuals; (2) the degradation products of ME cells or diffusible molecules of epithelial cells attract infiltration of immunoreactive cells (IRC) into the affected sites; (3) the direct physical contact between IRC and degenerated ME cells results in the discharge of digestive enzymes from IRC, causing focal disruptions in the ME cell layer; (4) focal disruptions in a given ME cell layer result in a localized loss of tumor suppressors and paracrine inhibitory function, a focal increase of permeability for oxygen, nutrients, and growth factors, and a localized increase of leukocyte infiltration, which facilitate the monoclonal proliferation of tumor progenitors, forming a biologically more aggressive cell cluster overlying the disrupted ME cell layer; (5) the direct physical contact between the newly formed cell cluster and stromal cells stimulates the production of tenascin and other invasion-associated molecules that facilitate tissue remodeling, angiogenesis, and epithelial-mesenchymal transition, providing a favorable micro-environment for proliferation and invasion. Our hypothesis differs from the enzyme theory in the stage of tumor invasion, the cellular origin of invasive lesions, the significance of IRC and stromal cells, and the potential approaches for treatment and prevention. If confirmed, our hypothesis could facilitate the early detection of specific individuals at increased risk to develop invasive breast cancer. More importantly, our hypothesis may facilitate development of novel approaches, including stimulating ME cell growth, neutralizing ME cell degradation products, manipulating the types and extent of IRC infiltration, and controlling the extent of stromal reactions, to combat tumor invasion.
Medical Hypotheses 02/2007; 69(6):1340-57. DOI:10.1016/j.mehy.2007.02.031 · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Benign prostatic hyperplasia and prostatic adenocarcinoma exhibit prominent zonal predilections. Basal cells from the transitional zone and from the peripheral zone are postulated to have different underlying biological properties. We studied basal cells in both prostatic zones.
Tissue microarrays (TMA) were prepared from 65 whole-mounted prostatectomy specimens with prostatic adenocarcinoma. The transitional zone and peripheral zone were sampled from each prostate. TMA sections were stained with a basal cell cocktail (CK 34betaE12 + p63). The immunostaining pattern and the morphology of basal cells were recorded.
Triangular-shaped basal cells were highlighted by CK 34betaE12 cytoplasmic and p63 nuclear staining. These basal cells had their long axis oriented perpendicular to the basement membrane and their apex toward the lumen interdigited between secretory luminal cells. This morphology was seen in the majority of peripheral zone benign prostatic glands (92.0%) but only a minority of transitional zone benign prostatic glands (18.0%). Basal cells of the transitional zone showed weak or absent CK 34betaE12 staining in 65.9% of glands while maintaining p63. All glands with high-grade prostatic intraepithelial neoplasia (HGPIN) contained the triangular basal cells. In addition, basal cell clusters were identified in 8.7% of peripheral zone glands and 5.2% of HGPIN glands.
Our results indicate that the basal cell morphology and the basal cell immunophenotype have a zonal variation. The finding of a unique morphology of basal cells and the presence of basal cell clusters in the peripheral zone suggests that the peripheral zone might be the stem/progenitor cell-rich area in the human prostates.
The Prostate 11/2007; 67(15):1686-92. DOI:10.1002/pros.20658 · 3.57 Impact Factor
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